Trifluoromethyl substituted dibenzxze-



United States Patent Ofifice 3,068,222 Patented Dec. 11, 1962 This invention relates to trifluoromethyl substituted H dibenz-[b,f]-azepines,10,l 1-dihydro-5H-dibenz-[b,f]- azepines and the S-dialkylaminoalkyl derivatives thereof. Further, this invention relates to novel processes for the preparation of trifiuoromethyl substituted SH-dibenz- [b,f]-azepines and 5-dialkylaminoalkyl-SH-dibenz-[b,f]- azepines.

The trifiuoromethyl substituted S-dialkylaminoalkyl- 5H-dibenz-[b,f]-azepines and the corresponding 10,11- dihydro compounds which are the subject of this invention have useful therapeutic activity, specifically as antiemetics, tranquilizers, calrnatives, antihistaminics, spasmolytics, antishock agents, antidepressants and potentiators of analgetics or anesthetics.

The novel trifiuoromethyl substituted S-dialkylaminoalkyl-SH-dibenz-[b,f]-azepines and the corresponding 10,11-dihydro compounds of this invention are represented by the general formula:

FORMULA 1 q IDII y 8 If 1 I r b '7 5 3 in i L} when Y represents CH -CH or CH=CH.

R represents hydrogen or trifiuoromethyl.

A represents a divalent, straight or branched lower alkylene chain, preferably containing 2 to 4 carbon atoms, separating the two nitrogens by at least 2 carbons, and

Z represents amino, monoalkylamino, dialkylamino, pyrrolidinyl, N-hydrogenpiperazinyl, N-alkylpiperazinyl, N hydroxyalkylenepiperazinyl, N alkanoyloxyalkylenepiperazinyl, N-benzoyloxyalkylenepiperazinyl, N-dialkylaminoalkylenepiperazinyl, N hydroxyalkyleneoxyalkylenepiperazinyl, N alkanoyloxyalkyleneoxyalkylenepiperazinyl, N-benzoyloxyalkyleneoxyalkylenepiperazinyl, N- hydroxyethoxyethoxyethylpiperazinyl or N-phenylalkylpiperazinyl.

The advantageous compounds of this invention are represented by the following formula:

FORMULAZ El cr A-Z when:

Y represents CH -CH or CH=CH.

R represents hydrogen or trifiuoromethyl.

A represents a divalent, straight or branched lower alkylene chain, preferably containing 2 to 4 carbon atoms,

separating the two nitrogens by at least 2 carbons, and

Z represents amino, methylamino, ethylamino, di methylamino, diethylamino, pyrrolidinyl, N-alkylpiperazinyl N-hydroxyalkylenepiperazinyl, N-alkanoyloxyalkylenepiperazinyl, N-hydroxyalkyleneoxyalkylenepiperazinyl,

-alkanoyloxyalkyleneoxyalkylenepiperazinyl and N-hydroxyethoxyethoxyethylpiperazinyl.

Preferred compounds of this invention are represented by the following formula:

FORMULA 3 CH VHCH -Z when:

Y represents CH CH R represents hydrogen or trifiuoromethyl.

R represents hydrogen or methyl, and

Z represents amino, methylamino, ethylamino, dimethylamino, diethylamino, pyrrolidinyl, N-alkylpiperazinyl, N-hydroxyalkylenepiperazinyl, N-alkanoyloxyalkylenepiperazinyl, N-hydroxyalkyleneoxyalkylenepiperazinyl, N-alkanoyloxyalkyleneoxyalkylenepiperazinyl and N-hydroxyethoxyethoxyethylpiperazinyl.

By the terms alkyl or alkanoyl where used herein alone or in combination with other terms, aliphatic groups are indicated; the alkyl groups having from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, and the alkanoyl groups having from 2 to 6 carbon atoms, preferably from 2 to 4 carbon atoms. When the term alkylene is used in connection with a carbon chain, except where otherwise specified, alkylene chains of from 2 to 6 carbon atoms, preferably 2 to 4 carbons are indicated. The term alkylene further indicates that a chain of at least 2 carbon atoms separate the oxygen or nitrogen atoms to which the alkylene chain is attached. The term dialkylamino when used in reference to thegeneric name represented in Formula 1 includes various heterocyclic amines attached to the alkylene side chain at the 5-position as outlined here above.

This invention also includes salts of the above defined bases formed with nontoxic organic and inorganic acids. These salts are easily prepared by methods known to the art. The base is reacted with either the calculated amount of organic or inorganic acid in aqueous miscible solvent, such as acetone or ethanol, with isolation of the salt by concentration and cooling or an excess of the acid in aqueous immiscible solvent, such as ethyl ether or chloroform, with the desired salt separating directly. Exemplary of such organic salts are those with maleic, fumaric, benzoic, ascorbic, pamoic, succinic, bismethylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzene sulfonic and theophylline acetic acids as well as with the 8-halotheophyllines, for example, 8-bromotheophylline. Exemplary of such inorganic salts are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids. Of course, these salts may also be prepared by the classical method of double decomposition of appropriate salts which is well-known to the art.

The starting materials for preparing the trifluoromethyl substituted 5-dialkylaminoalkyl-dibenzazepines and the corresponding 10,1l-dihydrodibenzazepines (also referred FORMULA 4 when:

Y represents GH -CH or CH=CH, and

R represents hydrogen or trifiuoromethyl, preferably in the 7-position.

The novel dibenzazepines of Formula 4 (Y is CH=CH) which are unsubstituted in the 5-position are prepared from the corresponding iminodibenzyls (Y is CH CH by dehydrogenation in accordance with the novel method of this invention. In this method, the iminodibenzyl is heated in the presence of a dehydrogenation catalyst. Exemplary of suitable catalysts are sulfur, selenium or, advantageously, the noble metals, such as palladium, ruthenium, iridium, rhodium and osmium which are preferably used in combination with a carrier such as charcoal, barium sulfate or silica gel. The metal content of the noble metal catalyst when preferably combined with a carrier will be from about 5 to about 50% by weight. The catalyst of choice is palladium on charcoal.

- This method can be carried out in a variety of ways, for example, the iminodibenzyl can be passed in the vapor phase through a glass column packed with the dehydrogenation catalyst. Such passage can be effected by distilling in the case of a liquid or by sublimation in the case of a solid. It is desirable for improving the contact properties of the catalyst to have said dehydrogenation catalyst loosely distributed on an inert dispersing medium, for example, sprinkled on glass wool. It is preferred to carry out the vaporization of the iminodibenzyl under reduced pressure. The product is isolated by cooling the upper end of the column and removing the material which collects. The solid is purified by recrystallization or chromatography with activated alumina to give the dibenzazepine.

Alternatively, the reaction may be run in a flask by heating the iminodibenzyl either alone or in a solvent such as diphenyl, diphenyloxide or dimethylaniline at elevated temperatures, preferably about 175 C. to about 300 C. with a catalyst as outlined above such as selenium, sulfur or palladium. The reaction product is then isolated by fractional crystallization or chromatography.

The novel S-unsubstituted iminodibenzyls of Formula 4 which are used to prepare the 5-dialkylaminoalkyliminodibenzyls and also as intermediates as outlined above, are readily obtained from the properly substituted diaminodibenzyl:

CHrCEa CHz-CHz This method is carried out by heating the diphosphate of the substituted 2,2'-diaminodibenzyl, alone or in the presence of polyphosphoric acid at approximately 280 C. for a short period of time, for example from 30 to 60 minutes.

The diaminodibenzyls are prepared by methods anal- 4 ogous to those in the prior art which are generalized in the following synthetic procedure:

aminoalkyl-5H-dibenz[b,f]-azepines and the corresponding 10,11-dihydro compounds represented by Formula 1:

Thus, the dibenzazepines and iminodibenzyls are alkylated with any reactive dialkylaminoalkyl ester containing the desired -A Z moiety such as a halide, preferably chloride or bromide, or an aryl sulfonate, preferably p-toluene sulfonate. The reaction is carried out advantageously by refluxing the reactants in a suitable inert aromatic solvent such as, preferably, benzene, toluene or xylene, in which at least one of the reactants must be soluble. A suitable acid-binding agent is usually included, such as an alkali metal amide, preferably sodium, potassium or lithium amide. Other suitable acid-binding agents are alkali metal hydrides, preferably sodium hydride or alkali metal aryl or alkyl compounds, preferably phenyl or octyl sodium. If an acid addition salt of the reactive dialkylaminoalkyl ester is used, a corresponding increase in the amount of acid-binding agent must be used.

The preferred method of alkylation, however, is to react the dibenzazepine or iminodibenzyl with a slight excess of a dialkylaminoalkyl chloride or bromide in the presence of sodium or potassium amide in refluxing benzene or toluene for from 30 minutes to 36 hours, preferably 3 to 24 hours.

The trifiuoromethyl substituted S-dialkylaminoalkyldibenzazepine or iminodibenzyl is isolated by cooling the reaction mixture and carefully adding an excess of water. The organic layers are extracted with dilute acid, preferably dilute hydrochloric acid. The acid extracts are combined, neutralized with dilute base and extracted with benzene. The dried benzene extracts are evaporated and the resulting residue. is optionally fractionally distilled under high vacuum or purified by a chromatographic procedure to give the desired base. In practice, the basic oil is usually dissolved in an organic solvent and converted into a stable salt by reacting the solution with a suitable organic or inorganic acid.

The trifluoromethyl substituted 5-(w-piperazinylalkyl)- dibenzazepines and iminodibenzyls are prepared advantageously by alkylating the dibenzazepine or iminodibenzyl with an w-haloalkylpiperazine having the free N-hydrogen of the piperaziuyl moiety replaced by an easily removed moiety, for example, a benzyl, carbobenzoxy, or acyl, preferably formyl group. The N-protective group is then removed under mild conditions, such as by weakly alkaline hydrolysis in the case of the preferred formyl group. The resulting trifluorornethyl substituted 5-(w-piperazinylalkyl)-dibenzazepine or iminodibenzyl is then further alkylated to form the various N-substituted piperazinyl compounds represented in Formula 1. Such methods of alkylation are by a reactive ester such as an alkyl halide in the presence of an acid binding agent as described above in an inert solvent such as benzene or xylene or by reaction with an alkylene oxide such as ethylene oxide in a lower alcohol. In addition, trifluoromethyl substituted 5-(N-alkyl-N-piperazinylalkyl)-dibenzazepines and iminodibenzyls having a terminal group on the N'-alkyl moiety capable of undergoing reaction, such as w-hydroxyalkyl, are optionally reacted with an acyl halide in the presence of an acidbinding agent to give, for example, N-acyloxyalkyl derivatives of trifluoromethyl substituted 5(w-piperazinylalkyD-dibenzazepines and corresponding irninodibenzyls.

Another synthetic route to trifiuoromcthyl substituted S-(w-piperrrzinylalkyl)-dibenzazepines and iminodibenzyls is by means of 5-(w-ester-alkyl)-dibenzazepines or iminodibenzyls which have a reactive end group on the S-alkyl chain, for example, an w-tosylate or w-ChlOro end group, which can be reacted with various amines to form primary, secondary or tertiary amines, for instance by refluxing the ester and amine in the presence of an acid binder for short periods.

The primary trifluoromethyl substituted S-(aminoalkyl)-dibenzazepines and iminodibenzyls are alternatively produced by reacting the S-unsubstituted compounds with an excess of acrylonitrile or in an inert solvent such as benzene in the presence of a catalytic amount of a strong base, such as a quaternary base, for instance benzyltrimethylammonium hydroxide. The resulting B- cyanoethyl compound is then reduced, for instance with lithium aluminum hydride to give the primary amine. Further alkylation by methods discussed heretofore of the primary amine gives other compounds of this invention.

The trifiuoromethyl substituted S-dialkylaminoalkyl- SH-dibenz-[b,f]-azepines and the corresponding 10,11-dihydro compounds of this invention may be advantageously prepared from substituted dibenzyls in an alternative manner, namely, by alkylating a 2-amino-2'-halodibenzyl under conditions identical with those described above for the S-alkylation of the dibenzazepines and iminodibenzyls and subsequently cyclizing the dibenzyl to form the alkylated iminodibenzyl. Dehydrogenation of the alkylated iminodibenzyls under conditions described hereabove gives the corresponding dibenzazepine compounds.

The above cyclization of a 2-dialkylamino-alkylamino- 2-halodibenzyl, with a dialkylaminoalkyl moiety which is inert under the conditions subsequently employed, is carried out by heating the compound in the presence of an acid-binding agent, present in at least an amount sufficient to neutralize the hydrohalic acid formed during the reaction. Exemplary of such acid-binding agents are the carbonates, such as sodium carbonate, sodium bicarbonate or preferably potassium carbonate. The reaction is run in a suitable, non-reactive organic solvent in which the reactants are at least partially soluble. EX- emplary are dioxane, dimethylaniline, diethylformamide, methylformamide, dimethylformamide or dimethylacetamide. Preferably, the solvent is dimethylformamide and other similar lower-carbon amides.

Optimum yields in this cyclization are obtained when catalytic amounts of copper or copper bronze powder are added, for instance up to 5% by Weight of the dibenzyl. The reaction mixture is advantageously heated at from about 100 to 220 C. for long periods, such as from 4 to 60 hours. Preferably, the reaction mixture is heated with stirring at the boiling point of the solvent for from about 8 to 24 hours. The reaction mixture is worked up by cooling, filtering and quenching in water. The separated product is washed and purified to give the desired iminodibenzyl.

The foregoing is a general description of the preparation of trifluoromethyl substituted 5H-dibenz-[b,f]-azepines by a novel dehydrogenation process, 10,1l-dihydro- SH-dibenz-[b.f]-azepines and the main synthetic routes by which these compounds may be converted into trifiuoromethyl substituted 5-dialkylaminoalkyl-SH-dibenz- [b,f]-azepines and the corresponding 10,11-dihydro derivatives.

Of particular advantage as preparative procedures for obtaining the novel compounds of this invention are the N alkylation of dibenzazepines and iminodibenzyls in the 5-position of the nucleus by a reactive dialkylaminoalkyl ester, and the dehydrogenation of 5-a1kylated iminodibenzyls by a suitable catalyst such as palladium on charcoal to yield the corresponding dibenzazepines.

It will be readily apparent to one skilled in the art that certain of the compounds of this invention, notably those in which A is represented by an aliphatic carbon chain branched so that an asymmetric carbon atom is formed may be present as optical isomers. The connotation of the general formulae presented herein is to include all isomers, particularly the separated d or 1 optical isomers as Well as the dl mixture of these isomers. If desired, the isomers may be separated for individual use by separation methods known to the art, such as fractional crystallization, for instance, of the d-tartrate salts of the 5-dialkylarninoalkylated derivatives. Alternatively, a synthesis starting with an optically active side chain may yield the desired optical isomer.

The following examples are not limiting but are illustrative of compounds of this invention and the procedures for their preparation and will serve to make fully apparent all of the compounds embraced by the general formula given above and the preparation thereof respectively.

Example 1 A solution of 41.0 g. of 2-nitro-4-trifiuoromethyltoluene (prepared from 4-trifluoromethylbenzaldehyde by reduction with amalgamated zinc and concentrated hydrochloric acid according to the general directions outlined for the Clemmenson Reduction in Organic Reactions, vol. 1, Chap. 7, p. 155, Roger Adams, Ed. and subsequent nitration of the resulting 4-trifiuoromethyltoluene by a standard procedure with a mixture of nitric acid and sulfuric acids) and 23.4 g. of amyl nitrite in 150 ml. of cyclohexane is added dropwise with stirring at 5 C. to a suspension of 13.6 g. of sodium ethoxide in 50 ml. of absolute ether. The mixture is stirred with cooling for six hours and for an additional four hours at room temperature. The reaction mixture is then treated with 200 ml. of Water, filtered and the solid recrystallized from alcohol to yield 2,2'-dinitro-4,4'-bistrifluoromethyldibenzyl.

A solution of 40.8 g. of 2,2'-dinitro-4,4'-bistrifluoromethyldibenzyl in 200 ml. of dioxane is hydrogenated in the presence of 10.0 g. of Raney nickel at 40 to 50 C. and four atmospheres pressure until the theoretical six mole ratio of hydrogen is taken up. The mixture is then heated on a steam bath to about -95 C. and the cata-.- lyst removed by filtration. Evaporation of the solvent gives 2,2'-diamino-4,4'-bistrifluoromethyldibenzyl. For the ensuing reaction, it is not necessary to isolate the free diamino compound. Thus, 43.2 g. of phosphoric acid is added to the above hot, filtered dioxane solution and the precipitate, after cooling, is filtered and washed to give the diphosphate.

A mixture of 10.8 g. of 2,2-diamino-4,4-bistrifluoromethyldibenzyl diphosphate and ml. of diphenyl ether is heated at 280 C. for 40 minutes. The reaction mixture is cooled and the separated solid Washed with dilute hydrochloric acid and Water to yield 3,7-bistrifluoromethyl-10,ll-dihydro-SH-dibenz [b,f]-azepine (3,7-bistrifluoromethyliminodibenzyl) Example 2 An electrically heated glass column is packed with 2.0 g. of 30% palladium on charcoal sprinkled on glass Wool and 10.0 g. of 3,7-bistrifluoromethyliminodibenzyl (prepared as in Example 1) is sublimed through it by increased heating at 0.2 mm. until sublimation slowly occurs. After tWo hours the reaction is completed and the material which collected in the upper part of the column (cooled by a Dry .lce bath) is removed. The crude product is purified by chromatography through alumina using benzene and chloroform to yield 3,7-bistrifluoromethyl- H-dibenz-[b,f]-azepine as orange-yellow crystals.

Example 3 To a mixture of 0.4 g. of sodium amide in 100 ml. of anhydrous toluene heated to reflux, is added 3.3 g. of 3,7- bistrifluoromethyl-SH-dibenz-[b,f]-azepine (prepared as in Example 2) dissolved in 200 ml. of hot toluene. The resulting mixture is stirred and refluxed for two hours. A solution of 1.3 g. of 3-chloro-l-dirnethylaminopropane in 25 ml. of toluene is then added and the refluxing continued for 17 hours, with stirring. The cooled reaction mixture is treated with 125 ml. of water, stirred for minutes and the separated organic layer extracted several times with dilute hydrochloric acid. The combined acidic extracts are made basic with 40% sodium hydroxide solution and extracted with benzene. Evaporation of the solvent gives the residual product, 3,7 bistrifluoromethyl 5 (3' dimethylaminopropyl) 5H dibenz- [b,f] azepine, which may be purified by chromatography through alumina, using benzene as the solvent.

Treating an ethyl acetate solution of the free base with an equimolar solution of maleic acid in ethyl acetate gives the maleate salt.

Example 4 A mixture of 0.6 g. of sodium amide and 4.9 g. of 3,7- bistrifluoromethyliminodibenzyl (prepared as in Example 1) in 300 ml. of toluene is heated to reflux. After two hours of refluxing with stirring, a solution of 1.9 g. of 3-chloro-l-dimethylaminopropane in 50 ml. of toluene is added and the refluxing continued for 18 hours. The cooled reaction mixture is worked up as described in Example 3 to yield 3,7-bistrifluoromethyl-10,1l-dihydro- 5 3 -dimethylaminopropyl -5H-dibenz- [bi] -azepine.

Example 5 A mixture of 6.6 g. of 3,7-bistrifluoromethyliminodibenzyl (prepared as in Example 1), 0.9 g. of sodium amide and 75 ml. of xylene is stirred and heated at reflux for one hour. A solution of 3.9 g. of 1-(3-chloropropyl)-4-methyl-piperazine in ml. of xylene is added and the mixture is refluxed for six hours. The cooled reaction mixture is treated with Water, extracted with dilute hydrochloric acid and the acid extracts are neutralized with aqueous ammonia. After benzene extraction and subsequent removal of the dried solvent in vacuo, the residue is purified by chromatography or molecular distillation to give 3,7-bistrifiuoromethyl-10,11-dihydro-5- [3 (4" methyl 1" piperazinyl) propyl] 5H dibenz [b,f] azepine.

A solution of the free base in ether is treated with ethereal hydrogen chloride to yield the dihydrochloride salt.

Example 6 A solution of 10.2 g. of 2-nitro-4-triflu0romethyltoluene (prepared as described in Example 1), 6.8 g. of 2-nitrotoluene and 11.7 g. of arnyl nitrite in 75 ml. of cyclohexane is slowly added to a stirred suspension of 6.8 g. of sodium ethoxide in ml. of absolute ether at 5 C.

8 The mixture is stirred at room temperature for 24 hours and then treated as in Example 1 to give 2,2-dinitro-4- trifluoromethyldibenzyl.

A mixture of 3.4 g. of 2,2'-dinitro-4-trifluoromethyldibenzyl and 1.0 g. of Raney nickel in 50 ml. of dioxane is hydrogenated at 40 to 50 C. and four atmospheres pressure until the theoretical amount of hydrogen is taken up. After heating the reaction mixture on a steam bath to about 95 C., the catalyst is filtered and 5.4 g. of phosphoric acid is added to the hot filtrate to give 2,2'-diamino- 4-trifluoromethyldibenzyl diphosphate.

4.8 g. of 2,2-diamino-4-trifluoromethyldibenzyl diphosphate is heated alone at 280 C. for 40 minutes and the cooled solid washed with dilute hydrochloric acid and Water to give 3-trifluoromethyliminodibenzyl.

Example 7 A suspension of 5.3 g. of 3-trifluoromethyliminodibenzyl (prepared as in Example 6), 0.9 g. of sodamide and 3.0 g. of 1-chloro-3-dimethylamino-Z-methylpropane in ml. dry xylene is stirred and heated at reflux for 15 hours. After cooling, the reaction mixture is treated with Water and the organic layer extracted with dilute hydrochloric acid. The acid extracts are neutralized and extracted with benzene. Removal of the solvent in vacuo gives 10,11 dihydro 5 (3' dimethylamino 2 methylpropyl) 3 trifiuoromethyl 5H dibenz [b,f]- azepine.

Example 8 A glass column is packed With 1.5 g. of 25% palladiumon charcoal sprinkled on glass wool. The column is electrically heated and 7.5 g. of 10,1l-dihydro-5-(3-dimethylamino 2 methylpropyl) 3 trifluoromethyl- 5H dibenz [b,f] azepine (prepared as in Example 7) is distilled through the column by heating at 0.5 mm. until distillation occurs. The upper part of the column is cooled and after four hours the reaction is completed. The material which collected is removed and chromatographed through alumina to give 5-(3'-dimethylarnino- 2 methylpropyl) 3 trifluoromethyl 5H dibenz- [bi] azepine.

A solution of the above free base in ether is treated with anhydrous hydrogen chloride gas to yield the hydrochloride salt.

Example 9 An electrically heated glass column is packed with 1.0 g. of 30% palladium on charcoal sprinkled on glass Wool and 5.0 g. of 3-trifluoromethyliminodibenzyl (prepared as in Example 6) is sublimed through it by increased heating at 0.2 mm. until sublimation occurs. The upper part of the column is cooled by a Dry Ice bath and the material which collected there is removed after two hours. The product is purified by chromatography through alumina to give 3-trifluoromethyl-SH-dibenz- [b,f]-azepine.

Example 10 A suspension of 2.6 g. of 3-trifiuoromethyliminodibenzyl (prepared as in Example 6), 0.6 g. of potassium amide and 1.3 g. of 2-chloro-l-dimethyl-aminopropane in 75 ml. of toluene is stirred and refluxed for 15 hours. The cooled reaction mixture is treated with water and extracted with dilute hydrochloric acid. The acid extracts are neutralized with ammonium hydroxide, ex-

tracted with benzene and the solvent evaporated in vacuo. The residue, which is a mixture of the two isomeric isopropyl compounds, is purified to give 10,11-dihydro-5-dimethylaminoisopropyl-3-trifluoromethyl-SH-dibenz- [b,f] azepine.

A solution of the free base in ethyl acetate treated With bismethylenesalicylic acid in ethanol solution gives the bismethylenesalicylate salt.

Example 11 A suspension of 13.2 g. of 3-trifluoromethyliminodi-.

benzyl (prepared as in Example 6) and 2.2 g. of sodamide in 150 ml. of xylene is heated at reflux for one hour with stirring. A solution of 9.7 g. of 1-(3'-chloropropyl)-4- methylpiperazine in 50 ml. of xylene is added and the mixture refluxed for six hours. The reaction mixture is cooled and worked up as described in Example to yield 10,11 dihydro 5 [3 (4 methyl 1" piperazinyl)- propyl] 3 trifluoromethyl 5H dibenz [b,f] azepine.

By treating a solution of the free base with hydrogen chloride gas the dihydrochloride salt is obtained.

Example 12 A suspension of 2.6 g. of 3-trifluoromethyl-SH-dibenz- [b,f]-azepine (prepared as in Example 9), 0.4 g. of sodium amide and 1.9 g. of Z-bromo-l-pyrrolidinylethane in 100 ml. of xylene is stirred and heated at reflux for twelve hours. Cooling the reaction mixture and working up as outlined in Example 3 yields 5-(2'-N-pyrrolidinylethyl)-3-trifiuoromethyl-SH-dibenz-[b,f]-azepine.

A solution of the free base in ether treated with glacial acetic acid furnishes the acetate salt.

Example 13 A stirred suspension of 6.6 g. of 3-trifluoromethyliminodibenzyl (prepared as in Example 6) and 1.1 g. of sodamide in 125 ml. of xylene is refluxed for 40 minutes. A solution of 5.2 g. of 1-formyl-4-(3'-chloropropyl)- piperazine in 25 ml. of xylene is added and the mixture is refluxed for 16 hours. The reaction mixture is treated with about 50 ml. of water and the separated organic layer extracted with dilute hydrochloric acid. The acidic extracts are made basic with ammonium hydroxide and fur ther extracted with benzene. Distillation of the solvent in vacuo gives the residual product, 10,11-dihydro-5-[3-(N- formylpiperazinyl) propyl] 3 trifluoromethyl 5H- dibenz-[b,f]-azepine.

Example 14 A solution of 57.4 g. of 10,1l-dihydro-S-[3'-(N-formylpiperazinyl) propyl] 3 trifluoromethyl 5H dibenz- [b,f]-azepine (prepared as in Example 13) in 200 ml. of ethanol and 109 ml. of water containing 13 ml. of 40% sodium hydroxide solution is heated at reflux for two hours. The ethanol is removed by distillation in vacuo on the steam bath and the residue is treated with benzene and water. The dried benzene layer is evaporated in vacuo and the residue vacuum distilled to give 10,11-dihydro-5- (3' piperazinylpropyl) 3 trifluoromethyl 5H dibenzb,f] -azepine.

Example 15 One equivalent of ethylene oxide is added to a solution of 3.9 g. of 10,11-dihydro-5-(3'-piperazinylpropyl)-3-trifluoromethyl-SH-dibenz-[b,f]-azepine (prepared as in Example 14) in 25 ml. of methanol and the mixture heated at reflux for one and one-half hours. The solvent is removed in vacuo to give the residual 10,11-dihydro-5-[3- (N-hydroxyethylpiperazinyl) propyl] 3 trifluoromethyl-5H-dibenz-[b,f]-azepine, which is dissolved in 50 ml. of benzene and treated with a solution of 1.5 g. of acetyl chloride in 15 ml. of benzene. The resulting mixture is refluxed for minutes, cooled and all solvents removed in vacuo to give the residual 5-[3-(N-acetoxyethylpiperazinyl) propyl] 10,11 dihydro 3 trifluoromethyl- 5H-dibenz-[b,f]-azepine monohydrochloride. This salt is dissolved in alcohol and reacted with isopropanolic hydrogen chloride to yield the dihydrochloride.

Similarly, a portion of the residual hydroxyethyl compound prepared as above is treated in a benzene solution with isocaproyl chloride to yield lO.1l-dihydro-5-[3'-(N- isocaproyloxyethylpiperazinyl) propyl] 3 trifluoromethyl-SH-dibenz- [b,f] -azepine dihydrochloride.

Example 16 A solution of 4.7 g. of 5-(3-hydroxypropyl)-3-trifluoromethyl-5H-dibenz-[b,f]-azepine p-toluene-sulfonate (prepared from the reaction of the sodio derivative of 3-trifiuorornethyl-SH-dibenz-[b,f] -azepine prepared as in Example 9 with -bromopropyl tetrahydropyranyl ether in xylene, removing the pyranyl group by careful hydrolysis with hydrochloric acid and acylating the y-hydroxy compound with excess p-toluene-sulfonyl chloride in pyridine) and 1.5 g. of butylamine in 30 ml. of ethanol is heated at reflux for ten hours. The solvent is removed from the reaction mixture and the residue is extracted with a waterchloroform mixture. The chloroform layer is extracted with dilute mineral acid and the extracts are neutralized with sodium carbonate solution. The crude product is extracted into ethyl acetate and the solution is heated with maleic acid to yield 5-(3'-buty1aminopropyl)-3-trifluoromethyl-5H-dibenz-[b,f]-azepine maleate.

Following the above procedure and using an excess of methylamine or ethylarnine in a sealed tube, 5-(3'-methylaminopropyl) 3 trifluoromethyl 5H dibenz [b,f]- azepine and 5-(3'-ethylaminopropyl)-3-trifluoromethyl- 5H-dibenz-[b,f]-azepine are obtained, respectively.

Example 17 Example 18 A solution of 2.4 g. of 10,1l-dihydro-S-[3"-(N-hydroxyethoxyethylpiperazinyl) propyl] 3 trifluoromethyl- 5H-dibenz-[b,f]-azepine (prepared as in Example 17) in 50 ml. of dry benzene is treated with 0.8 g. of acetyl chloride. The reaction mixture is stirred at room temperature for three hours and then poured into water, neutralized and extracted with benzene. The solvent is evaporated and an alcoholic solution of the residue reacted with anhydrous hydrogen chloride gas to give 5-[3"-(N-acetoxyethoxyethylpiperazinyl) propyl] 10,11 dihydro 3- trifiuoromethyl-SH-dibenz-[b,f]-azepine dihydrochloride.

Similarly, by acylating with butyryl chloride, 5-[3'-(N- butyryloxyethoxyethylpiperazinyl) propyl] 10,11 dihydro 3 trifluoromethyl 5H dibenz [b,f] azepine dihydrochloride is obtained.

Example ,19

A suspension of 21.8 g. of 10,11-dihydro-5-(3'-piperazinylpropyl) 3 trifluoromethyl 5H dibenz [b,f]- azepine (prepared as in Example 14), 2.4 g. of sodarnide and 9.2 g. of 2-bromo-l-dimethylaminoethane in 250 ml. of benzene is stirred and refluxed for six hours. Upon treating the reaction mixture as described in Exampe 5, the product, 10,1l-dihydro-S-[3-(N-dirnethylaminoethylpiperazinyl) propyl] 3 trifluoromethyl 5H dibenz- [b,f]-azepine is obtained.

Following the same procedure as above and alkylating with 4-bromo-l-diethylaminobutane, 5-[3-(N-diethylamino butylpiperazinyl)-propyl]-10,1 1-di-hydr0-3 -trifluoromethyl-5H-dibenz-[b,f] -azepine is prepared.

Example 20 A suspension of 16.4 g. of 3,7-distrifluoromethyl-SH-dibenz-[b,f]-azepine (prepared as in Example 2), 2.1 g. of sodamide and 13.6 g. of N-carbethoxy-6-(ot-chloro-B- methylpropyl)-piperazine (prepared by reacting N-carbethoxypiperazine with S-bromo-Z-methyl-propyl chloride) in 200 ml. of toluene is heated at reflux for 17 hours. Working up the reaction mixture as described in Example 11 13 yields -[3'-(N-carbethoxypiperazinyl)-2'-methylpropyl] -3,7-bistrifluoromethyl-5H-dibenz- [b,f] -azepine.

A solution of 8.1 g. of the carbethoxy compound prepared above in 75 ml. of aqueous ethanol and 2.5 ml. of 40% sodium hydroxide solution is refluxed for four hours. The solvent is evaporated in vacuo and the residue treated with benzene-water. Evaporation of the extract yields 3,7 bistrifluoromethyl-5-(2'-methyl-3-piperazinylpropyl) -5 H-dibenz- [b,f] -azepine.

Treating a solution of the free base in ethyl acetate with an ethanolic solution of mandelic acid furnishes the dimandelate salt.

Example 21 To a solution of 4.7 g. of 3,7-bistrifluoromethyl-5-(2'- methyl 3 piperazinylpropyl)-5H-dibenz-[b,f]-azepine (prepared as in Example in ml. of ethanol, one equivalent of ethylene oxide is added and the mixture is refluxed for one and one-half hours. The solvent is removed and a solution of the residue in 100 ml. of benzene is treated with a solution of 1.6 g. of acetyl chloride in 20 ml. of benzene. The resulting mixture is refluxed for minutes and then worked up as in Example 15 to yield 3,7 bistrifluoromethyl-S-[2-methyl-3-(N-acetoxyethylpiperazinyl)-propyl] -5H dibenz-[bfi] -azepine dihydrochloride.

Similarly, by reacting the 3,7-bistrifluoro-methyl-5-[2'- methyl 3' (N-hydroxyethylpiperazinyl)-propyl] -5H-dibenz-[b,f]-azepine obtained as above with benzoyl chloride in benzene solution, 3-7-bistrifluoromethyl-5-[2'- methyl 3' (N-benzoyloxyethylpiperazinyl)-propyl] -5H- dibenz-[b,f]-azepine dihydrochloride is obtained.

Example 22 A solution of 1.5 g. of lithium aluminum hydride in 100 ml. of anhydrous ether is added dropwise to a stirred suspension of 3.8 g. of 3,7-bistrifluorornethyl-5-(2-cyanoethyl)-5H-dibenz-[b,f]-azepine (prepared by reacting 3,7 bistrifluoromethyl-5H-dibenz-[b,f]-azepine, obtained as described in Example 2, with acrylonitrite in the presence of benzyltrimethylammonium hydroxide) in 250 m1. of anhydrous ether, and the mixture is refluxed for 24 hours. The cooled reaction mixture is treated with methanol to destroy the metal complex and filtered. The filtrate is evaporated and they residue extracted with dilute mineral acid. The acid extracts are neutralized, extracted with chloroform and upon distillation of the solvent in vacuo, 5 (3'-aminopropyl)-3,7bistrifluoromethyl5H-dibenz- [b,f] -azepine is isolated.

Example 23 A suspension of 14.0 g. of 3,7-bistrifluoromethyl-5-(2'- methyl 3 piperazinylpropyl)-5H-dibenz-[b,f]-azepine (prepared as in Example 20), 5.7 g. of 3-bromopropanol and 6.2 g. of potassium carbonate in 200 ml. of xylene is. stirred and refluxed for five hours. Working up the reaction mixture as described in Example 17 yields 3,7-bistrifluoromethyl 5-[2-methyl 3'-(N- -hydroxypropylpiperazinyl -propyl] -5H-dibenz- [b,f] -azepine.

A solution of 5.4 g. of the free base and 2.1 g. of butyryl chloride in 100. ml. of benzene is allowed to stand at room temperature for 17 hours and then worked up as in Example 18 to give 3,7-bistrifluoromethyl-5-[2'-methyl-3- (N 'y butyryloxypropylpiperazinyl)-propyl] -5H-dibenz- [b,f] -azepine dihydrochloride.

Example 24 A suspension of 2.2 g. of S-trifluoromethyliminodibenzyl (prepared as in Example 6), 0.4 g. of sodamide and 2.4 g. of 3-chloro-l-(N-benzylpiperazinyl)-propane in 100 ml. of toluene is heated at reflux for 17 hours. Following the work-up procedure of Example 5, 5-[3- (N benzylpiperazinyl) propyl]-10,1l-dihydro-3-trifluoromethyl-SH-dibenz-[b, f]-azepine is isolated.

Similarly, by employing 3-chloro-l-(N-w-phenylbutyl- 12 piperazinyl) propane, 10,11-dihydro-5-[3'-(N-w-phenylbutylpiperazinyl) propyl] 3-trifluoromethyl-SH-dibenz- [bi] -azepine is obtained.

Example 25 A stirred suspension of 9.4 g. of 3,7-bistrifluoromethyl- 5 (2-methyl-3-piperazinylpropyl)-5H-dibenz-[b,f]-azepine (prepared as in Example 20), 4.5 g. of n-hexyl iodide and 8.3 g. of potassium carbonate in 150 ml. of xylene is heated at reflux for eight hours. The reaction mixture is filtered and the filtrate washed with water, dried and concentrated. The residual product is dissolved in ethyl acetate and reacted with two equivalents of maleic acid to yield 3,7-bistrifluoromethyl-5-[2-methyl-3'-(N-hexy1- piperazinyl -propyl] -5H-dibenz- [b,f] -azepine dimaleate.

Example 26 A suspension of 4.7 g. of 10,11-dihydro-5-(3'-piperazinylpropyl) 3 trifluoromethyl-SH-dibenz-[b,f] -azepine (prepared as in Example 14), 3.4 g. of 4-bromo-4-hydroxybutyl ether (prepared from 4,4-dihydroxybutyl ether by careful treatment with one equivalent of hydrobromic acid) and 2.5 g. of potassium carbonate in 150 ml. of xylene is refluxed for 24 hours. Working up the reaction mixture as in Example 17, the product 10,11-dihydro 5 [3'-(N-hydroxybutoxybutylpiperazinyl)-propyl]- 3-trifluoromethyl-SH-dibenz-[b,f]-azepine is obtained.

A solution of 2.9 g. of the free base and 1.4 g. of benzoyl chloride in 50 ml. of dry benzene is allowed to stand at room temperature for 24 hours and then treated as described in Example 18 to yield 5-[3'-N-benzoyloxybutoxybutylpiperazinyl)-propyl]-10,1 1-dihydro-3- trifluoromethyl-SH-dibenz- [b,f] -azepine dihydrochloride.

Similarly, acylating with acetyl chloride as above yields 5-[3 (N-ace'toxybutoxybutylpiperazinyl)-propyl]-10,l1- dihydro 3-trifluoromethyl-SH-dibenz-[bi] -azepine dihydrochloride.

Example 27 A suspension of 15.6 g. of 10,1l-dihydro-5-(3'-piperazinylpropyl) 3 trifluoromethyl-SH-dibenz-[b,f]-azepine (prepared as in Example 14), 9.0 g. of w-bromohexanol and 8.3 g. of potassium carbonate in 250 ml. of xylene is stirred and heated at reflux for 24 hours. The reaction mixture is worked up as described in Example 17 to yield 10,11 dihydro-5-[3'- (N-w-hydroxyhexylpiperazinyl-propyl] -3 -trifluoromethyl-SH-dibenz- [b,f] -azepine.

A solution of 12.8 g. of the free base and 7.0 g. of benzoyl chloride in 150 ml. of benzene is allowed to stand at room temperature for 17 hours and then worked up in as in Example 18 to give 5-[3'-(N-w-benzoyloxyhexylpiperazinyl) propyl] 10,11-dihydro-3-trifluoromethyl-Sl-Ldibenz- [b,f] -azepine dihydrochloride.

Similarly, acylating the above hydroxy compound with acetyl chloride in a benzene solution yields 5[3'-(N-w acetoxyhexylpiperazinyl) propyl]-10,11-dihydro-3-trifluoromethyl-SH-dibenz-[b,f]-azepine dihydrochloride.

Example 28 A mixture of 2.6 g. of 3-trifluoromethyl-5H-dibenz- [b,f]-azepine (prepared as in Example 9), 0.4 g. of sodium amide and 1.6 g. of 3-chloro-l-diethylaminopropane in ml. of toluene is heated at reflux with stirring for 15 hours. Upon working up the cooled reaction mixture as described in Example 3, the product 5-(3'-diethylaminopropyl) 3 trifluoromethyl 5H dibenz [b,f]- azepine is isolated.

Example 29 A mixture of 6.6 g. of 3-trifluoromethyliminodibenzyl (prepared as in Example 6), 1.0 g. of sodamide and 3.3 g. of 3-chloro-l-dimethylaminopropane in 250 ml. of toluene is refluxed for 12 hours. The reaction mixture is treated as described in Example 3 to yield 10,11-dihydro 5 (3-dimethylaminopropyl) 3 trifluoromethyl- SH-dibenz- [b,f] -azepine.

A mixture of 12.6 g. of 10,11-dihydro-5-[3-(N-hydroxyethylpiperazinyl)-propyl] 3 trifluoromethyl 5H- dibenz-[b,f]-azepine dihydrochloride (prepared by treating the N-hydroxyethyl free base prepared as in Example 15 with an excess of isopropanolic hydrogen chloride) and 4.5 g. of thionyl chloride in 100 ml. of chloroform is refluxed for five hours. The solvent is removed by evaporation to give a solid, 10,1l-dihydro-S-[3'-(N-[3-chloroethylpiperazinyl)-propyl]-3-trifiuoromethyl 5H dibenz- [b,f]-azepine dihydrochloride.

A mixture of 14.8 ml. of fi-hydroxyethyl ether and 25 ml. of benzene is heated over an azeotropic trap until 10 ml. of benzene is collected. To the cooled residue 0.35 g. of sodium is added and refluxing continued until the sodium has disappeared. The dihydrochloride salt of the chloroethyl intermediate prepared above (2.6 g.) is added and the mixture is heated and stirred on the steam bath for three hours, allowing the benzene to evaporate. The residue is stirred at room temperature for 18 hours, then quenched with water. The mixture is extracted with benzene. The extracts are taken through dilute hydrochloric acid and then neutralized to give an oil which is extracted into chloroform. The chloroform is removed and the residue dissolved in ethyl acetate is treated with an excess of maleic acid to give 10,1l-dihydro- 5 [3'-(N-hydroxyethoxyethoxyethylpiperazinyl)- propyl] -3-trifluoromethyl-SH-dibenz- [b,f] -azepine dimaleate.

This application is a continuation-in-part of Serial No. 688.442 filed October 7, 1957.

What is claimed is:

1. A chemical compound having the following formula:

2. Chemical compounds having the following formula:

CHE-CH2 CHzCHz OHz-N Nalkylene-hydroxy in which the alkylene moiety has from 2 to 6 carbon atoms.

3. A chemical compound having the following fora mula:

CHz-CH? 1 1-0 Fa \N 4. Chemical compounds having the following formula:

OER-CH2 Fa \N JHaGHrOHr-N N-al'kylene-O-alkanoyl in which the alkylene and alkanoyl moieties each have from 2 to 6 carbon atoms.

1d 5. A chemical compound having the following formula:

dagomom-N N-oH2onZ-0-o o113 6. A chemical compound having the following formula:

CHz-CH 7. A chemical compound having the following formula:

OH2-OH2 JHzCH2OHzN NCH2CH2(O CH2CH2)2OH 8. Chemical compounds of the class consisting of a free base and the nontoxic acid addition salts thereof, the free base having the following formula:

in which R is a member selected from the group consisting of hydrogen and trifluoromethyl; R is a member selected from the group consisting of hydrogen and methyl; and Z is a member selected from the group consisting of amino, methylamino, ethylamino, dimethylamino, diethylamino, pyrrolidinyl, N-alkylpiperazinyl, N-hydroxyalkylenepiperazinyl, N-alkanoyloxyalkylenepiperazinyl, N-hydroxyalkyleneoxyalkylenepiperazinyl, N-alkanoyloxyalkyleneoxyalkylenepiperazinyl and 'N-hydroxyethoxyethylpiperazinyl; said alkyl moiety having 1 to 6 carbon atoms and each of said alkanoyl and alkylene moieties having 2 to 6 carbon atoms.

9. A chemical compound having the following formula:

OHrOH:

\ CFB 10. A chemical compound having the following formula:

ens-0H2 CFa- OF References Cited in the file of this patent UNITED STATES PATENTS 2,813,857 Schindler et al Nov. 19, 1957 2,889,322 Jacob et a]. June 2, 1959 2,921,069 Ullyot Ian. 12, 1960 

8. CHEMICAL COMPOUNDS OF THE CLASS CONSISTING OF A FREE BASE AND THE NONTOXIC ACID ADDITION SALTS THEREOF, THE FREE BASE HAVING THE FOLLOWING FORMULA:
 9. A CHEMICAL COMPOUND HAVING THE FOLLOWING FORMULA: 